This invention relates to 2-unsaturatedalkythio-pen-2- em-3-carboxylic acids and their pharmaceutically acceptable salts and esters which are useful as antibiotics I: ##STR2## wherein R.sup.l, R.sup.2, R.sup.3 and R.sup.4 are independently selected from: hydrogen; substituted and unsubstituted; alkyl, alkoxyl and alkenyl having from 1-6 carbon atoms; cycloalkyl having 3-6 carbon atoms; halo (chloro, fluoro, bromo); aralkyl having from 7-14 carbon atoms, such as benzyl; aryl, such as phenyl; heteroaryl, heterocyclyl and heterocyclyalkyl, wherein the heterocyclic ring comprises 4-6 members, one or more being selected from oxygen, nitrogen and sulfur and the alkyl moeity has from 1-6 carbon atoms; wherein the substituent or substituents on R.sup.l, R.sup.2, R.sup.3 and R.sup.4 are selected from halo (chloro, bromo, fluoro, iodo), hydroxyl, alkoxyl, cyano, carboxyl, carbamoyl, amino, and the above recited values for R.sup.1, R.sup.2, R.sup.3 and R.sup.4 ; n is 0 or 1; W is an electron withdrawing group, which may be selected from --COR.sup.5 CN, and SO.sub.2 C.sub.6 H.sub.5 ; wherein R.sup.5 is hydrogen; substituted and unsubstituted: alkyl having 1-6 carbon atoms; aryl and aralkyl having 6-14 carbon atoms, such as phenyl and benzyl; cycloalkyl having 3-6 carbon atoms; heteroaryl, heterocyclyl and heterocyclylalkyl, wherein the heterocyclic ring comprises 4-6 members, one or more being selected from oxygen, nitrogen, and sulfur and the alkyl moiety has from 1-6 carbon atoms; or R.sup.5 may be: --OR.sup.6, --NR.sup.7 R.sup.8, or --SR.sup.9 ; wherein R.sup.6 is hydrogen; or substitued and unsubstituted: alkyl or alkenyl having 1-6 carbon atoms, or a group which defines --CO.sub.2 R.sup.6 as a pharmaceutically acceptable ester, wherein R.sup.6 is, for example, phthalidyl, or 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl; R.sup.7 and R.sup.8 are independently selcected from: hydrogen, and substituted and unsubstituted: alkyl having 1-6 carbon atoms; aryl, aralkyl having 7-14 carbon atoms, such as benzyl; and heteroaryl, heterocyclyl, and heterocyclylalkyl (as defined above): R.sup.9 is selected from the same group comprising R.sup.7 and R.sup.8, but excludes hydrogen; wherein: the substitutent or substituents on the above-defined radical groups are selected from: halo (chloro, bromo, fluoro, iodo), hydroxyl, alkoxyl, cyano, carboxyl, carbamoyl, amino, and the above recited values for R.sup.l, R.sup.2, R.sup.3 and R.sup.4 ; R.sup.3 may also be W; when the unsaturated moiety attached to the exocyclic sulfur atom is acetylenic, then R.sup.3 and R.sup.4 are nonexistent and W is a previously defined.
This invention also relates to a process for preparing the penem antibiotic of structure I, above. This process involves the reaction of an appropriately substituted 2-thiopenam 1: ##STR3## with a Michael reagent in the presence of base; wherein R.sup.l and R.sup.2 are as previously defined and R is a removable protecting group.
This invention also relates to a process for preparing 6- and 6,6-disubstituted-2-substituted thio-pen-2-em-3-carboxylic acids Ia: ##STR4## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and W are as previously defined, and their pharmaceutically acceptable salts and esters which are useful as antibiotics.
The common intermediate for the preparation of novel compounds I and compounds Ia, the 2 thioxopenam 1, above, is described in co-pending concurrently filed U.S. patent application Ser. No. 460,729 of F. P. DiNinno, W. J. Leanza and R. W. Ratcliffe filed concurrently with the present application. The cited application is fully incorporated herein by reference to the extent that it teaches the preparation of intermediates; and penem antibiotics; which utility is common to the final antibiotic compound of the present invention.
There is a continuing need for new antibiotics. For, unfortunately, there is no static effectiveness of any given antibiotic; because continued wide scale usage selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics continues.
Thus, it it an object of the present invention to provide a novel class of antibiotics which are useful in animal and human therapy and in inanimate systems. These antibiotics are active against a broad range of pathogens which representively include both Gram-positive bacteria such as S. aureus, Strep. pyogenes, and B. subtilis, and Gram-negative bacteria such as E. coli, Pseudomnas, Proteus morganii, Serratia, and Klebsiella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their nontoxic pharmaceutically acceptable salts and esters; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated.